Cited by 236GDF15 and Related BiomarkersRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys

Xiong, Yumei, Walker, Kenneth, Min, Xiaoshan, Hale, Clarence, Tran, Thanhvien, Komorowski, Renee, Yang, Jerry, Davda, Jasmine +8 more·2017·Science Translational Medicine

Abstract

In search of metabolically regulated secreted proteins, we conducted a microarray study comparing gene expression in major metabolic tissues of fed and fasted ob/ob mice and C57BL/6 mice. The array used in this study included probes for ~4000 genes annotated as potential secreted proteins. Circulating macrophage inhibitory cytokine 1 (MIC-1)/growth differentiation factor 15 (GDF15) concentrations were increased in obese mice, rats, and humans in comparison to age-matched lean controls. Adeno-associated virus-mediated overexpression of GDF15 and recombinant GDF15 treatments reduced food intake and body weight and improved metabolic profiles in various metabolic disease models in mice, rats, and obese cynomolgus monkeys. Analysis of the GDF15 crystal structure suggested that the protein is not suitable for conventional Fc fusion at the carboxyl terminus of the protein. Thus, we used a structure-guided approach to design and successfully generate several Fc fusion molecules with extended half-life and potent efficacy. Furthermore, we discovered that GDF15 delayed gastric emptying, changed food preference, and activated area postrema neurons, confirming a role for GDF15 in the gut-brain axis responsible for the regulation of body energy intake. Our work provides evidence that GDF15 Fc fusion proteins could be potential therapeutic agents for the treatment of obesity and related comorbidities.

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Crossref · 10.1126/scitranslmed.aan8732

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38 of 38 references verified0 citation errors · 0 not checkable

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  • GDF-15 levels are altered in obese mice, rats, and humans compared to matched lean controls.

    “Altered GDF-15 levels in comparison to matched lean controls have been frequently reported in obese mice, rats, and humans (32, 105).”
  • Exogenous administration of recombinant murine or human GDF-15 induces weight loss in different animal models.

    “In line with these studies, exogenous administration of recombinant murine or human GDF-15 induced weight loss in different animal models (26, 32, 40, 41, 107).”
  • Elevated circulating GDF-15 levels are associated with more severe disease or higher mortality in people with DM2, insulin resistance, hemodialysis, cachexia, cardiovascular diseases, COPD, VTE, cancer, or obesity.

    “Elevated circulating GDF-15 levels have been associated with more severe disease or higher mortality in people with DM2, insulin resistance, hemodialysis, cachexia, cardiovascular diseases, chronic obstructive pulmonary disease (COPD), venous thromboembolism (VTE), cancer, or obesity (28–34).”

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Authors
Xiong, Y., Walker, K., Min, X., Hale, C., Tran, T., Komorowski, R., Yang, J., Davda, J., Nuanmanee, N., Kemp, D., Wang, X., Liu, H., Miller, S., Lee, K. J., Wang, Z., & Véniant, M. M.
Affiliations
  • Amgen (United States) (US)
  • Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Corresponding author
Véniant, Murielle M.
Venue
Science Translational Medicine
Published
2017-10-18
Volume
9
Issue
412
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
OpenAlex
W2765137069
Cited by
236
References
38
Citations by year
2026: 20 · 2025: 28 · 2024: 25 · 2023: 35 · 2022: 32 · 2021: 23 · 2020: 31 · 2019: 24 · 2018: 16 · 2017: 2
FWCI
17.45
Type
journal article
Language
en
Open access
closed
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
GDF15, MIC-1, obesity, Fc fusion protein, adeno-associated virus gene therapy, dietary intake, body weight, gut-brain axis, gastric emptying, food preferences, secreted proteins, Macaca fascicularis, structure-guided protein engineering
MeSH terms
Dependovirus, Animals, Diet, Food Preferences, Gastric Emptying, Humans, Macaca fascicularis, Male, Mice, Inbred C57BL, Mice, Obese, Neurons, Obesity, Receptors, Fc, Recombinant Fusion Proteins, Up-Regulation, Rats, Sprague-Dawley, Crystallography, X-Ray, Growth Differentiation Factor 15

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